Lin Siying, Niu Hongshen, Zhang Yuqi, Gai Kexin, Brown Ryan, Brown Ashley, Shen Jian, Xu Ziyang, Shah Ravi K, Schmeling Jessica L, Vargas-Cortes Marlenny, Zamora Anthony E, Kohwi-Shigematsu Terumi, Fan Jie, Zhang Bin, Cui Weiguo
Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Department of Microbiology and Immunology, Medical College of Wisconsin, Milwaukee, WI, USA.
Nat Immunol. 2025 Aug 22. doi: 10.1038/s41590-025-02257-w.
Stem-like progenitor CD8 T (T) cells sustain cytotoxic immunity during chronic infection and cancer through quiescence, multipotency and self-renewal, hallmarks shared with memory T cells. However, how these properties are maintained under persistent antigen stimulation remains unclear. Here we identify the genomic organizer SATB1 as selectively enriched in both T and memory CD8 T cells. Given its role in promoting quiescence in hematopoietic stem cells, we hypothesized that SATB1 supports CD8 T cell stemness. Using CD8 T cell-specific CRISPR deletion of the Satb1 gene, we show that SATB1 is essential for maintaining T cells during chronic lymphocytic choriomeningitis virus infection and for memory CD8 T cell formation during acute infection. Multi-omic profiling revealed that SATB1 regulates the chromatin accessibility, transcriptional activity and genome architecture of stemness-associated genes including Tcf7, Bach2 and Myb. These findings reveal a critical role for SATB1 in preserving the transcriptional and epigenetic programs that sustain the stem-like state of antigen-specific CD8 T cells.
干细胞样祖细胞CD8 T（T）细胞在慢性感染和癌症期间通过静止、多能性和自我更新维持细胞毒性免疫，这些特征与记忆T细胞相同。然而，在持续抗原刺激下这些特性是如何维持的仍不清楚。在这里，我们确定基因组组织者SATB1在T细胞和记忆CD8 T细胞中均选择性富集。鉴于其在促进造血干细胞静止方面的作用，我们假设SATB1支持CD8 T细胞干性。使用Satb1基因的CD8 T细胞特异性CRISPR缺失，我们表明SATB1对于慢性淋巴细胞性脉络丛脑膜炎病毒感染期间维持T细胞以及急性感染期间记忆CD8 T细胞形成至关重要。多组学分析表明，SATB1调节包括Tcf7、Bach2和Myb在内的干性相关基因的染色质可及性、转录活性和基因组结构。这些发现揭示了SATB1在维持抗原特异性CD8 T细胞干细胞样状态的转录和表观遗传程序中的关键作用。
